During the last few years, we have created new rodent Parkinson?s disease (PD) models that mimic the progressive disease development in PD patients. With these models, we have elucidated the novel mechanisms of microglial activation that lead to inflammation-mediated neurodegeneration. For the last year, the major effort was the development of novel anti-inflammatory therapy for PD. Information generated from the role of microglia in inflammation-related neurodegeneration has provided insights for us to develop a series of novel anti-inflammatory and neuroprotective agents. Unique from the conventional strategies for developing anti-inflammatory drugs, which often target a specific pro-inflammatory factor, our approach is to prevent the over-production of the majority of pro-inflammatory factors through the inhibition of the over-activation of microglia, which would prevent the subsequent inflammatory process. Furthermore, we have discovered several small molecules, including peptides and alkaloids, which are both anti-inflammatory and neuroprotective at femtomolar concentrations. In addition to their potential therapeutic benefits, the discovery of femtomolar-acting peptides also offers valuable insight to the potential physiological mechanisms governing microglial activation and DA neuron survival in the substantia nigra.